The present invention relates to a process for the preparation of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-ylacetic acid (ML 3000) and to a novel polymorph of ML 3000 which is designated as polymorph A.
ML 3000 is a promising inhibitor of cyclooxygenase and 5-lipoxygenase and is thus suitable for the treatment of disorders of the rheumatic type and for the preventive treatment of allergically induced disorders, for this see, for example, Drugs of the Future 1995, 20 (10):1007-1009. A possible route for preparation is also found in this publication. Further preparation possibilities are described in EP-A-397175, WO95/32970, WO95132971, WO95/32972, Archiv der Pharmazie 312, 896-907 (1979); and 321, 159-162 (1988), J. Med. Chem. 1994 (37), 1894-1897, Arch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997). In all these syntheses, the construction of the pyrrolizine parent structure is carried out according to the method shown in the reaction scheme: 
The reaction is carried out in methylene chloride, ethanol or diethyl ether. The hydrogen bromide formed in the reaction is trapped by addition of aqueous sodium bicarbonate solution.
The introduction of the acetic acid radical into position 5 is then carried out by reaction with ethyl diazoacetate or ethyl oxalyl chloride and subsequent hydrolysis or hydrolysis and reduction of the keto group with hydrazine.
Arch. Pharm. 312, 896-907 (1979) describes the following reaction: 
The reaction is carried out in benzene as a solvent. The COCOCl group, is then not converted into the acetic acid group, however, but reacted with diethylamine.
WO95/32970, WO95/32971 and WO95/32972 describe the introduction of the acetic acid radical into compounds which are structurally related to ML-3000 by reaction of these pyrrolizine compounds with oxalyl chloride or ethyl oxalyl chloride and subsequent reduction with hydrazine and potassium hydroxide (Huang Minlon variant of the Wolff-Kishner reduction). More detailed information on the experimental procedure is found only in Example 5C of WO95/32971. The reaction of the pyrrolizine compound with oxalyl chloride is then carried out in THF. Water and hydrazine hydrate are added to the reaction product and, the tetrahydrofuran is distilled off, the residue is treated with diethylene glycol and with potassium hydroxide and heated to 140xc2x0 C. with simultaneous removal of the water. The reaction mixture is subsequently treated with water, acidified and the precipitated carboxylic acid is taken up in diethyl ether. The product is purified by stirring the ethereal solution for some time over a drying agent, such as anhydrous sodium sulfate or magnesium sulfate, and allowing it to stand, then filtering off the water-saturated sulfate and finally evaporating the ether in the presence of heat. The substance crystallizing from the mother liquor on concentration is collected and dried.
For the industrial preparation of ML 3000, the introduction of the acetic acid radical using oxalyl chloride is preferred. However, it has been shown that after the above reaction in the previous process for the isolation and purification of the crude material the yield decreases severely and a number of decomposition products are newly formed in the purification step and additionally during the drying, so that a further laborious purification of the ML 3000, e.g. by recrystallization, is necessary in order to obtain pharmaceutical quality.
In the preparation process already mentioned, compounds structurally analogous to ML 3000 were purified and crystallized by the following methods.
In J. Med. Chem. 1994, 37, 1894-1897, the ethanolic/alkaline solution of the sodium salt of ML 3000 obtained from the hydrolysis of the ethyl ester is acidified with phosphoric acid and extracted with a mixture of 3 parts of diethyl ether and 1 part of methylene chloride. The solid which remains after drying over sodium sulfate and after stripping off the solvent mixture is resuspended using diisopropyl ether, filtered off and dried. For the preparation of ML 3000, reference is made to Arch. Pharm. 321, 159-162 (1988) (for discussion see below).
In Arch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997), heterocyclic structural analogs of ML 3000 which are formed from 2-oxoacetic acid precursors according to the Huang-Minlon method are obtained by concentrating the eluates obtained from a short silica gel column using diethyl ether.
In Arch. Pharm. 321, 159-162 (1988), the ethyl esters of some acids structurally related to ML 3000 are hydrolyzed in ethanol KOH, after the hydrolysis the acids are liberated from the aqueous/ethanolic mother liquor of the potassium salts by means of 6% strength phosphoric acid and taken up in diethyl ether. After volume reduction, the acids are adsorbed therefrom on neutral alumina. After ether elution of the neutral impurities, the carboxylic acids are desorbed from the mineral support by the action of aqueous sodium dihydrogenphosphate solution and in turn taken up in diethyl ether. This second diethyl ether extract is concentrated until it crystallizes, the crystals are separated off and, after addition of pentane to precipitate a second crystal fraction, the volume of the ethereal mother liquor is again reduced.
In the thesis of Kiefer (Frankfurt, 1992), for the preparation of an analogous pyrrolizin-5-yl-acetic acid the corresponding 2-oxoacetic acid is subjected to the Huang-Minlon reduction method. Before the liberation of the pyrrolizin-5-ylacetic acid contained in the reaction mixture as a potassium salt, the neutral to alkaline impurities and contaminants are removed by a preliminary extraction of the aqueous/alkaline product phase with ethyl acetate. Only then is the carboxylic acid precipitated by means of 6N HCl and taken up in diethyl ether. The diethyl ether extracts are washed with water, dried and the solvent is completely removed until a crystalline solid is present, which is then washed with cold diethyl ether.
The crystalline powder samples of ML 3000 prepared according to the previously known methods were measured by means of X-rays in powder refractometers and the refractograms, the powder spectra, were compared with one another. The substance samples were additionally investigated using the differential scanning calorimetry method (DSC) or using the thermogravimetric method (TGA). The powder refractometry measurements and the DSC measurements show that after crystallization from diethyl ether the substance is initially formed as an ether solvate in the crystalline form of rods. On crystallization from ethyl acetate, a solvate with ethyl acetate is analogously formed in the form of rhombi. It has been shown that these solvates are unstable. They decompose in vacuo and/or at elevated temperatures with only incomplete release of the bound solvent to give largely amorphous substances which, however, still contain residual solvent and in which increased amounts of decomposition substances can be detected after drying. For the solvates, characteristic desolvation temperature changes are found by means of DSC technology.
Crude ML 3000, which is obtained as a potassium salt by the hydrazine process and which is then precipitated from the reaction mixture rendered acidic with mineral acid, also contains hydrazine, by-products and decomposition products (decarboxylation product and also dimer) as a contaminant in addition to the poorly water-soluble potassium salts. This necessitated additional purification operations. For example, to remove the hydrazine components, the crude crystalline acid thus had to be washed a number of times with dilute mineral acids or its solution had to be extracted in order to lower the hydrazine content in the pure substance into the range of harmless residual amounts.
None of the processes published up to now yielded a material unrestrictedly suitable for administration to humans.
The present invention is therefore based on the object of making available a process for the preparation of ML 3000 in which ML 3000 is obtained in high purity and pure, defined crystalline form.
Surprisingly, it has now been found that this object is achieved if the corresponding pyrrolizine compound is reacted with oxalyl chloride and hydrazine and the reaction product is subjected to a special work-up. Moreover, it has been found that during the work-up a novel polymorphous ML 3000 (polymorph A) is formed.
The present invention therefore relates to a process for the preparation of the compound of the formula I (ML 3000) 
where the compound of the formula III 
is reacted with oxalyl chloride and the product obtained is treated with hydrazine and an alkali metal hydroxide in the aqueous phase at elevated temperature, after treatment is complete a three-phase system is produced by addition of an ether which is not miscible or only limitedly miscible with water and the compound of the formula I is obtained by acidifying the middle phase.